Diphenyloxamic acid derivatives



3,306,902 DIPHENYLGXARHC ACID DERIVATIVES Milton Wolf, 1208 Lotus Lane, West Chester, Pa. 19380, and Francis Greek, 7334 Valley Ave., Philadelphia, Pa. 19128 No Drawing. Filed July 15, 1964, Ser. No. 382,945 9 Claims. (Cl. 260-268) ing formula:

-Hydrohalide where A is selected from the group of:

wherein X is oxygen; NH; or sulfur; Z is hydrogen, (lower) alkyl having up to 4 carbon atoms or phenyl; K is hydrogen or (lower) alkyl; R and R may be the same or different and represent either H, alkyl having up to 4 carbons; phenyl(lower) alkyl, such as phenethyl; phenyl; halogen; alkoxy having up to 4 carbon atoms; alkylthio in which the alkyl moiety has up to 4 carbons; sulfamyl; alkylsulfamyl in which the alkyl moiety has up to 4 carbon atoms, carbalkoxy having up to 4 carbon atoms; acyl having up to 4 carbon atoms, anilino, cyano, nitro or halo (lower) alkyl. Y is amino or dialkylamino in which the alkyl moiety has up to 4 carbon atoms. R and R may be the same or difierent and can be: hydrogen, (lower) alkyl, lower alkoxy, phenyl, and n is an integer ranging from 1 to 4.

The novel compounds made available by the present invention are prepared by the process illustrated by the following equation:

United States Patent 0 ice In the above formulas, R, R and A have the meaning previously set forth.

In practising the process outlined above, a diphenyloxamidic acid chloride or bromide (II) prepared, for example, by the method of R. Stolle, J. prakt. Chem., 128, 1 (1930) is reacted with an aminoalcohol or a diamine represented by Formula III. This reaction is carried out generally .by adding a solution of a diphenyloxamidic acid halide in an inert and preferably anhydrous solvent such as benzene, methylene chloride, ether or tetrahydrofuran to a solution of a compound of Formula 111 in a similar solvent. Substantially equimolar amounts of the reactants are employed in this reaction which proceeds exothermically with some vigor. After the initial reaction subsides, the reaction mixture is refluxed at its reflux temperature to complete the reaction (usually around 15 minutes). The compounds are usually recovered in the form of their hydrohalides such as their hydrochlorides. In this form, they are pharmaceutically acceptable. If desired, the compounds may be converted in known manner to their other acid addition salts with, for example, fumaric, maleic or sulfuric acid.

The following examples serve to illustrate but do not limit the invention:

Example 1.1-diphenyloxam0yl-4-methylpiperazine hydrochloride A solution of diphenyloxamidic acid chloride (2.60 g., 0.010 m.) in anhydrous ether (40 ml.) is added rapidly to a solution of l-methylpiperazine (1.00 g., 0.010 m.) in anhydrous ether (25 ml.). There is an exothermic reaction, and a colorless solid separates. After the initial reaction subsides, the mixture is refluxed for 15 minutes, cooled and the colorless solid collected by filtration, washed with anhydrous ether (50 ml.), dried at 50 C./ house vac. The yield of colorless needles is 2.60 g. (72.2%), M.P. 237-240 C. (uncorr.). Recrystallization of the crude product from absolute ethanol gives colorless needles (2.10 g., 58.3%), M.P. 251-252 C. (uncorr.).

Analysis.-Calcd. for C H ClN O C, 63.42; H, 6.16; N, 11.68; Cl, 9.85. Found: C, 63.31; H, 6.11; N, 11.24; Cl, 10.1.

Example 2.Diphenyl0xamic acid, Z-aimelhylamino-lmethylethyl ester, hydrochloride Diphenyloxamidic acid chloride (2.60 g., 0.010 m.) in methylene chloride (15 ml.) is added in a single portion to a solution of 1-dimethylamino-2-propanol (1.03 g., 0.010 m.) in methylene chloride (15 ml.). After a mild exothermic reaction, the mixture is refluxed for 5 minutes then concentrated in vacuo. The residual gum crystallizes on trituration with a mixture of ether-ethylacetate. The product is collected by filtration, dried over P 0 in a vacuum desiccator; yield, 3.05 g. (84.3%), M.P. 149 C. (uncorr.). Recrystallization of the crude product from acetone-hexane gives colorless prisms (2.75 g., 76.0%), M.P. 147-148 C. (uncorr.).

Analysis. Calcd. for C19H23C1N2031 C, H, 6.37; N, 7.72. Found: C, 62.67; H, 6.58; N, 7.88.

Example 3.-N-(Z-diethylaminoethyl)-N,N- diphenyloxamide Diphenyloxamidic acid chloride (3.85 g., 0.0144 In.) is added in a single portion to a solution of N,N-diethylethylenediamine (1.72 g., 0.0148 m.) in anhydrous benzene (30 ml.). A strong exothermic reaction occurs with the separation of an oil. After the initial reaction subsides, the mixture is refluxed for 15 minutes, cooled, and the solid product collected by filtration, washed with benzene, dried at 50 C./house vac. The crude product (4.50 g., 83.4%), M.P. ISO-182 C. (uncorr.), is recrystallized from isopropyl alcohol with the aid of decolorizing carbon to obtain colorless prisms (3.70 g., 68.6%), M.P. 188-189 C. (uncorr.).

Analysis. Calcd. for C H C1N O C, 63.90; H, 6.97; N, 11.18. Found: C, 63.70; H, 7.04; N, 11.43.

Example 4.N'-(3-diethylaminopropyl)-N,N- diphenyloxamide hydrochloride A solution of N,N-diethyl-1,3-propanediamine (2.56 g., 0.0193 m.) in tetrahydrofuran (25 ml.) is added dropwise to a magnetically stirred solution of diphenyloxamidic acid chloride (5.0 g., 0.0193 in.) in tetrahydrofuran (25 ml.). After the addition is complete, the mixture is refluxed for one half hour, cooled, and the crude product collected by filtration, washed with ether, dried at 50 C./house vac. The yield of colorless solid is 6.43 g. (85.2%), M.P. 175.5l79.5 C. (uncorr.). Recrystallization of the crude product from isopropyl alcohol atfords colorless prisms, 5.17 g. (68.4%), M.P. 19l.0-191.5 C. (uncorr.).

Analysis. Calcd. for C21H23C1N302i C, H, 7.24; N, 10.78. Found: C, 64.90; H, 7.50; N, 10.58.

Example 5 .Diplzenyloxamic acid, 2-(1 -pyrrolidinyl) ethyl ester hydrochloride The reaction of diphenyloxamidic acid chloride (5.00 g., 0.0193 m.) with 2-pyrrolidinoethanol (2.24 g., 0.0193 m.) in a manner similar to that of Example 4 yields the title compound (6.57 g., 90.8%), M.P. 115-l18 C. (uncorr.). Recrystallization of the crude product from acetone-hexane yields colorless prisms (3.85 g., 53.2%), M.P. 135-136 C. (uncorr.).

Analysis. Calcd. for C20H23C1N203: C, H, 6.18; N, 7.47. Found: C, 64.12; H, 6.15; N, 7.39.

Example 6 .N-(4-methyl-1 -piperazinyl) -N ',N diphenyloxamide hydrochloride The reaction of diphenyloxamidic acid chloride (5.00 g., 0.0193 m.) with 1-amino-4-methylpiperazine (2.24 g., 0.0193 m.) in a manner similar to that of Example 4 yields the title compound (6.70 g., 92.6%), M.P. 286.5- 287.0 C. (uncorr.). Recrystallization of the crude product from methanol-ethanol gives colorless needles (5.28 g., 73.0%), M.P. 2865-2870 C. (uncorr.).

Analysis. Calcd. for C19H23C1N021 C, H, 6.18; N, 14.94. Found: C, 60.73; H, 6.16; N, 14.70.

Example 7.Diphenyloxamie acid, 3-diethylaminopropyl ester hydrochloride The reaction of diphenyloxamidic acid chloride (5.00 g., 0.0193 in.) with 3-diethylamino-l-propanol (2.52 g., 0.0193 In.) in a manner similar to that of Example 4 gives the title compound (6.27 g., 83.4%), M.P. 146.0- 148.5' C. (uncorr.). Recrystallization of the crude product from isopropyl alcohol yields colorless prisms (4.88 g., 65.0%), M.P. 149.5-150.0 C. (uncorr.).

Analysis. Calcd. for C H ClN O C, 64.52; H, 6.96; N, 7.17. Found: C, 64.52; H, 6.79; N, 6.91.

Example 8.Diplzenyloxamic acid, 3-dimethylaminopropyl ester hydrochloride The reaction of diphenyloxamidic acid chloride (5.00 g., 0.0193 in.) with 3-dimethylamino-1-propa11ol (1.99 g., 0.0193 m.) in a manner similar to that of Example 4 yields the title compound (6.02 g., 86.2%), M.P. 134- 135 C. (uncorr.). Recrystallization of the crude product from tetrahydrofuran pentane gives colorless prisms (2.18 g., 31.2%), M.P. 135.0136.5 C. (uncorr.).

Analysis.Calcd. for C H ClN O C, 62.89; H, 6.39; N, 7.72. Found: C, 62.77; H, 6.38; N, 7.75.

4 Example 9.Diphenyloxamic acid, 1-methyl-4-piperidinyl ester hydrochloride The reaction of diphenyloxamidic acid chloride (5.00 g., 0.0193 m.) with 4-hydroxy-l-methylpiperidine (2.20 g., 0.0193 m.) in a manner similar to that of Example 4 gives the title compound (7.20 g., 99.5%), M.P. 150.0157.5 C. (uncorr.). Recrystallization of the crude product from isopropyl alcohol yields colorless prisms (4.61 g., 63.8%), M.P. 196.0197.0 0. (uncorn).

Arzalysis.Calcd. for cgoHzzclNzogi C, H, 5.93; N, 7.49. Found: C, 64.15; H, 6.23; N, 7.52.

Example 10.1-diphenyloxamyl-4-plzenylpiperazine hydrochloride The reaction of diphenyloxamidic acid chloride (5.00 g., 0.0193 In.) With l-phenylpiperazine (3.13 g., 0.0193 m.) in a manner similar to that of Example 4 afiords the title compound (5.88 g., 72.4%), M.P. 195.0-198.0 C. (uncorr.). Recrystallization of the crude product from isopropyl alcohol gives colorless prisms (4.68 g., 57.5%), M.P. l97.020l.0 C. (uncorr.).

AnaIysis.-Calcd. for C H ClN O C, 68.33; H, 5.73; N, 9.96. Found: c, 68.62; H, 5.62; N, 10.21.

Example 11.Diphenylthioloxamic acid, Z-(diethylamino) ethyl ester hydrochloride The reaction of diphenyloxamidic acid chloride (5.00 g., 0.0193 m.) with 2-diethylaminoethanethiol (2.57 g., 0.0193 m.) in a manner similar to that of Example 4 yields the title compound (5.46 g., 72.2%), M.P. 176.0- 179.5 C. (uncorr.). Recrystallization of the crude product from isopropyl alcohol gives colorless prisms (3.24 g., 42.8%), M.P. l89.0l90.0 C. (uncorr.).

AnaIysis.-Calcd. for C H ClN O S: C, 61.14; H, 6.41; N, 7.13. Found: C, 61.04; H, 6.38; N, 7.01.

Example 12.3,5-dimethyl-1-diphenyloxamoylpiperazine hydrochloride Reactants Products Diphenyloxamic acid bromide and piperazme.

Diphenyloxamic acid chloride and 2-arninoethauethiol.

(p-Ethylphenyl)phenyloxamic acid chloride and l-methylpiperazure.

Bis (p-chlorophenyl) oxamic acid chloride and l-methylpiperazine.

(o-Phenethylphenyl)phenyloxamic acid chloride and l-ethyl piperazine.

(m-Butoxyphenyl) phenyloxarnic acid chloride and l-propyl piperazine.

(p-Sulfamylphenyl)phenyloxarnic acid chloride and l -methylpipcrazme.

(p-EthylsullnrnylphcnyDphenyloxamic acid chloride and 1- rncthylpiperazine.

(o-Carbethoxyphenyl)phenyloxamic acid chloride and l-mcthylpiperazine.

(p-Acetylphenyl) phenyloxarnic acid chloride and l-methylpiperazmc.

(o-Anilinophenyl)phenyloxamic acid chloride and l-methylpiperazme.

l-diphenyloxamoylpiperazine.

Diphenyloxamic acid, 2-an1inoethylthioester.

l-(p-ett' ylphcnyl)-phenyloxamoyl 4-n1etl1ylpiperazine.

1-[bis(p-chlorophenyl) oxamoyl]- 4-methylpip erazine.

1-[(0-ph enethylphenyl) -phenyloxamoyl1-4-ethyl piperazine.

1-[(m-butoxyphenyl)phenyloxamoyl]-4-propyl piperazine.

1-[(p-sulfarnylphenyl)-pl'enyloxamoy11-4-methylpipcraziue.

1-[(p-ethylsultamylphenyD-phenyloxamoyH-i-methyl piperazine.

l-l(o-carbethoxyphenyl)-phcnyl oxamoyl]-4-methylpipcrazinc.

1-[(p-z1cetylphenyl) phenyloxamoyl]-4-methy1piperazine.

1-[(o-an1linophenyl)-pheny1oxamoyl]-4-rnethylpiperazine.

Reactants Products (o-Cyanophenyl)phenyloxamic acid chloride and l-methylpiperzine. (m-Butoxymhenyl)phenyloxamic acid chloride and l-propylpiperazine. (p-Suliamylphenyl)phenyloxamic acid chloride and l-methylpiperapropanol. (p-Ethylsulfamyl)diphenyloxamidic acid chloride and 2-pyrrolidino ethanol. (o-Carbethoxy)-d1phenyloxam1d1c acid chloride and 1-amino-4- propylpiperazine. Bis(p-tolyl)oxarnic acid and methyl piperazine. (m-Bntyrylphenyl)phenyloxamic acid chloride and l-rnethylpiperazine. 2,2-dirnethylamiuo l-phenylethanol and diphenyloxamidic acid chloride. 5,Shimethylamino-Lpentanol and diphenyloxamic acid chloride.

1-[(o-cyanophenyl)phenyloxamoyl]-4-methylpiperazine.

l-[(m-nitrophenyl) phen yloxamoyl]-4-methylpi perazine.

1-[(p-dichloromethylphenyl)phenyloxamoyl1-4methylpiperazinc.

l-[bis(p-chlorophenyl)oxamoyl]-4- methylpiperazine.

1-[(o-phenethylphenyDphenyloxamoyH-et-ethylpiperazine.

1-[(mbutoxyphenyl) phenyloxamoyl]+propylpiperazine.

1-[(p-suliamylphenyl) phenyloxamoyl]-4-methylpipe1azine.

1-[(o-carbobutoxyphenyl)phenyloxamoyl]+methylpiperazine.

Diphenyloxamic acid, 3-(1-pyrrolidinyl) propyl ester.

N -(4-butyl-l-piperaz inyl) N ,N

diphenyloxamide.

3,4,c-tributyl-l-diphenyloxamoyl piperazme.

Diphenyloxarnic acid, l-hutyl-ipiperidinyl ester.

Diphenylthioloxamic acid, 2-(dibutylamino)ethyl ester.

l-(o-phenethyl)-diphenylthioloxamic acid, Z-(dimethylamino) ethyl ester.

l-(m-bntoxy)-diphenylthioloxamic acid, 2-(di propylamino)ethyl ester. 1-(oethylmercapto)-diphenyl thioloxamic acid, S-(dimethylamino) propyl ester. l-(p suliamyl)-diphenyloxamic acid, 3-(l-pyrrolidinyl)propyl ester. l-(ethylsulfamyl)-diphenyloxamic acid, Z-(I-pyrrolidinyl) ethyl diphenyl oxam 1-bis(p-tolyl) oxamoylA-methyl piperazme.

l-(p-butyrylphenyl) phenyl oxamoyl-emethylpiperazine.

Diphenyloxamio acid, (2,2'dimethylamino-l-phenyDethyl ester.

Diphenyloxamic acid (5,5-dimethylamino) pentyl ester.

The compounds of this invention can be administered with pharmaceutically acceptable inert carriers in a wide variety of oral or parenteral unit dosage forms containing 25, 100, 250 or 500 mg. of active ingredients for the symptomatic adjustment of the dosage to the individual patient, or in admixture with other active compounds.

The present invention also includes the process of bringing the compounds thereof into a form suitable for 6 therapeutic administration by associating them with liquid or solid, pharmaceutically acceptable carriers.

What is claimed is: 1. A member selected from the group consisting of a compound of the formula:

wherein A is selected from the group consisting of wherein Y is selected from the group consisting of amino and di(lower alkyl)amino; Z is selected from the group consisting of hydrogen, lower alkyl and phenyl; K is selected from the group consisting of hydrogen and lower alkyl; R and R are each selected from the group consisting of hydrogen, lower alkyl, phenyl lower alkyl, halogen, lower alkoXy, lower alkyl thio, sulfamyl, lower alkylsulfamyl, lower carbalkoxy, lower alkanoyl, anilino, cyano, nitro and halo lower alkyl; R and R are each selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and phenyl, and n is an integer from one to four; and the pharmaceutically acceptable acid addition salts thereof.

2. 1-dipheny1oXamoyl-4-(lower) alkyl piperazine.

3. N'-(2-di(lower) alkylaminoethyl)-N,N-diphenyl- Oxamide.

. l-diphenyloxamoyl-l-methylpiperazine. N'-(2-diethylaminoethyl)-N,N-dipheny1oxamide. N'-(3-diethylaminopropyl)-N,N-diphenyloxamide. N-(4-methyl-l-piperazinyl)-N',N'-diphenyloxamide.

1-diphenyloxamoyl-4-phenylpiperazine. 3,5-dimethyl-l-diphenyloxamoyl piperazine.

No references cited.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

J. W. ADAMS, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3,306,902 February 28, 1967 Milton Wolf et a1,

n the above numbered patthat error appears i ould read as It is hereby certified d that the said Letters Patent sh ent requiring correction an corrected below In the heading to the printed specification, lines 3 to 5, for "Milton Wolf, 1208 Lotus Lane, West Chester, Pa, 19380, and Francis Greek, 73-34 Valley Ave. Philadelphia, Pa. 19128" read Milton Wolf, West Chester, and Francis Greek, Philadelphia, Pa,, assignors to American Home Products Corporation, New York,

N, Y a corporation of Delaware a Signed and sealed this 28th day of November 1967o (SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr. Attesting Officer Commissioner of Patents 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 